The gut mucosal barrier is disrupted in HIV disease, resulting in increased systemic exposure to microbial products such as Lipopolysaccharide (LPS) and bacterial DNA. Perturbations in the gut barrier in HIV disease may stem from deletion of CD4+ T cells, loss of Th17 helper cells, disruption of enterocyte homeostasis and diminished humoral immunity. The consequences of a permeable gut barrier in HIV infection are not fully understood, although there is evidence that exposure to microbial products could contribute to chronic immune activation in HIV disease and may also play a role in limiting CD4+ T cell reconstitution during highly active antiretroviral therapy (HAART). Here, we consider the possibility that microbial translocation also could play an important role in B cell perturbations that are characteristic of HIV infection. These perturbations include polyclonal B cell activation, B cell dysfunction and depletion of the memory B cell subset. Memory B cell dysfunction and depletion are the focus of our proposed studies as our preliminary data demonstrate that the TLR4 ligand LPS, and HIV virions cooperate to induce memory B cell death in peripheral blood cell cultures in vitro, enhanced memory B cell apoptosis ex vivo and plasma levels of LPS in vivo, and decreased level of recall antibody EndoCab (neutralizing antibody against LPS) in vivo from HIV+ donors. Therefore, we hypothesize that heightened microbial translocation and HIV replication collaborate to drive peripheral memory B depletion. We hypothesize that certain immune signatures of B cell subsets will predict reduced antibody responsiveness to vaccination (especially for T cell independent recall antigens) in HIV infection. We propose to explore the mechanisms responsible for TLR/HIV-mediated memory B cell death and to investigate in vivo correlates of these findings including identifying the predictors for reduced vaccine (both T cell dependent and independent antigens) responsiveness in HIV infection. By determining the mechanisms of B cell depletion and perturbations in HIV disease, we may be better able to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation. PUBLIC HEALTH RELEVANCE: The purpose of the present study is to explore the mechanisms of peripheral memory B cell loss and reduced vaccine responsiveness in HIV infection. The goals of the present study are better to design interventions that will potentially improve immune responses to vaccines, reduce selected opportunistic infections (e.g. pneumococcus) and perhaps slow disease progression by restoring the immunologic barrier that protects against microbial translocation.